Searching for New Chemotherapies for Tropical Diseases: Ruthenium-Clotrimazole Complexes Display High in Vitro Activity against Leishmania major and Trypanosoma cruzi and Low Toxicity toward Normal Mammalian Cells

Eight new ruthenium complexes of clotrimazole (CTZ) with high antiparasitic activity have been synthesized, cis,fac-[(RuCl2)-Cl-II(DMSO)(3)(CTZ)] (1), cis,cis,trans-[(RuCl2)-Cl-II(DMSO)(2)(CTZ)(2)] (2), Na[(RuCl4)-Cl-III(DMSO)(CTZ)] (3), Na[trans-(RuCl4)-Cl-III(CTZ)(2)] (4), [Ru-II(eta(6)-p-cymene)Cl-2(CTZ)] (5), [Ru-II(eta(6)-p-cymene)(bipy)(CTZ)][BF4](2) (6), [Ru-II(eta(6)-p-cymene)(en)(CTZ)][BF4](2) (7), and [Ru-II(eta(6)-p-cymene)(acac)(CTZ)][BE4] (8) (bipy = bipyridine; en = ethlylenediamine; acac = acetylacetonate). The crystal structures of compounds 4-8 are described. Complexes 1-8 are active against promastigotes of Leishmania major and epimastigotes of Trypanosoma cruzi. Most notably, complex 5 increases the activity of CTZ by factors of 110 and 58 against L. major and T. cruzi, with no appreciable toxicity to human osteoblasts, resulting in nanomolar and low micromolar lethal doses and therapeutic indexes of 500 and 75, respectively. In a high-content imaging assay on L. major-infected intraperitoneal mice macrophages, complex 5 showed significant inhibition on the proliferation of intracellular amastigotes (IC70 = 29 nM), while complex 8 displayed some effect at a higher concentration (IC40 = 1 mu M).